“We have created a mechanism that makes it practically impossible for a real genius to appear. In my own field the biochemist Fritz Lipmann or the much-maligned Linus Pauling were very talented people. But generally, geniuses everywhere seem to have died out by 1914. Today, most are mediocrities blown up by the winds of the time.”

-Erwin Chargaff, 1985.

Erwin Chargaff, (1905-2002) a biochemist born in Austria, became interested in DNA earlier than most. In the 1930s, while he was working with the bacteria Rickettsi, he became aware of nucleic acids, and decided to educate himself about them.

In 1944, after Oswald Avery published his paper detailing the transforming principle of the Pneumococcus bacteria, Chargaff decided to devote his laboratory almost entirely to the chemistry of nucleic acids. Experimenting with these delicate substances was not an easy task, but eventually a chromatographic technique was developed that would allow for the separation and analysis of the base rings in DNA. This work would later lead to the development of Chargaff’s Rules, the topic of today’s post.

The guanine-cytosine base pair.

DNA has two main structural components – a backbone made up of sugar and phosphate groups, and a series of bases found in the middle of the molecule. There are four different bases found in DNA: Adenine (A), Cytosine (C), Guanine (G), and Thymine (T). These four bases can be divided into two categories, pyrimidines and purines. The pyrimidine bases, Cytosine and Thymine, contain only one ring, while the purine bases, Guanine and Adenine, contain two rings. In the DNA structure, the bases pair complementarily, meaning that a purine base will bind with a pyrimidine base. More specifically, Adenine binds with Thymine and Cytosine binds with Guanine.

The adenine-thymine base pair.

Although this information is now considered fundamental biology, it wasn’t fully understood until after Watson and Crick discovered the structure of DNA in 1953. However, Chargaff’s research in the late 1940s had suggested that the four bases paired in the manner described above.

When Chargaff first decided to devote his laboratory to nucleic acids, he allowed a postdoctoral student named Ernst Vischer to choose his research program from a list of suggested topics. Vischer decided to analyze the purines and pyrimidines in nucleic acids, and went to work developing the chromatographic technique so crucial to isolating the bases. Although his technique was rather crude, it did the trick and Vischer achieved great success. The results of the base analysis showed that the amounts of Adenine and Thymine were about equal, and also that the amounts of Guanine and Cytosine were about equal. Eventually, Chargaff came to the conclusion that in a single molecule of DNA, Guanine/Cytosine = Adenine/Thymine = 1. This concept would later become known as Chargaff’s Rules.

Chargaff’s Rules were officially announced in a lecture delivered in June of 1949 and were first published in May of 1950. However, Linus Pauling had heard about the ratios much earlier – straight from Chargaff in late 1947, while traveling to England for his six-month stay as a professor at Oxford University. Pauling, who considered the trip by ship across the Atlantic Ocean with his family to be a vacation, did not pay attention to what Chargaff told him.

Crellin Pauling, the youngest child of Linus and Ava Helen Pauling, mentioned the remarkable background to the incident in a speech given during a symposium to celebrate Pauling’s life that was held here at Oregon State University in 1995.

Over time Chargaff mentioned his work to individuals beyond Pauling. In the spring of 1952, Chargaff met James Watson and Francis Crick. A prickly character, it is clear that Chargaff didn’t think much of the duo. In his truly remarkable autobiography Heraclitean Fire: Sketches from a Life before Nature, Chargaff calls Watson and Crick “a variety act” and further describes them as:

One 35 years old (Crick), with the looks of a fading racing tout. . .an incessant falsetto, with occasional nuggets gleaming in the turbid stream of prattle. The other (Watson), quite undeveloped. . .a grin, more sly than sheepish. . .a gawky young figure.

He further notes that:

I never met two men who knew so little and aspired to so much. They told me they wanted to construct a helix, a polynucleotide to rival Pauling’s helix. They talked so much about ‘pitch’ that I remember I wrote it down afterwards, ‘Two pitchmen in search of a helix.’

Regardless of what he thought of them, Chargaff still mentioned his work to Watson and Crick. The information, although published almost two years earlier, seemed to be new to the pair.

Though Chargaff himself didn’t speculate much on his rules, and Pauling completely ignored them, they did prove to be extremely useful to Watson and Crick. With this new knowledge, the feedback they had received from Rosalind Franklin and Maurice Wilkins, and data obtained through their own research, Watson and Crick were soon able to correctly deduce the structure of DNA.